Fluid delivery devices and methods

ABSTRACT

Methods, systems, and devices are provided for generating a mist. In one embodiment, a fluid delivery device is provided that includes a housing, a fluid vaporizer disposed within the housing and configured to receive fluid and to produce an aerosol mist of liquid particles from the fluid, and a pump configured to accelerate the aerosol mist produced by the fluid vaporizer. Methods are provided for producing a mist, and the methods can include delivering a fluid to a fluid vaporizer that generates a first mist. The fluid vaporizer delivers the mist to a pump that generates a second mist from the first mist.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/609,585, filed on May 31, 2017 and entitled “Fluid Delivery Devicesand Methods,” which is a continuation of U.S. patent application Ser.No. 15/173,142 (now U.S. Pat. No. 9,700,686), filed on Jun. 3, 2016 andentitled “Fluid Delivery Devices and Methods,” which claims priority toU.S. Provisional Patent Application No. 62/170,216, filed Jun. 3, 2015and entitled “Fluid Delivery Devices and Methods,” which areincorporated by reference herein in their entireties.

FIELD

Methods, systems, and devices are provided for delivering fluid to asurface containing cells.

BACKGROUND

Fluid delivery for localized delivery of molecules into tissues in apatient and transfection and/or introduction of materials into cellssuffers from limitations of existing technologies. Delivering a fluidcontaining an agent to a localized spot within a patient is an importantfluid delivery method for a variety of treatments, such as localizeddelivery of antibiotics, the treatment of diabetes, various geneticdisorders, novel cancer treatments, and an expanding number of cosmeticuses. Specifically, transdermal delivery refers to delivering an agentby crossing a skin of the patient. As an example, transdermal deliveryof antibiotics is preferably used in treating skin and soft tissueinfections. This localized treatment can be especially important wheretraditional oral and/or intravenous delivery mechanisms are ineffectiveor less-than-ideal, or a combination of different delivery devices andmethods can be used together to improve delivery results. It can also beimportant to deliver large molecules such as plasmids or vectors intocells over a localized surface, such as into skin cells.

Using a transdermal delivery approach for localized delivery is superiorto hypodermic injections because hypodermic injections can be painful,risk infection via needle reuse or misuse, and can create medical waste.

There are several approaches to transdermal delivery, each of whichrange in terms of effectiveness for particular applications. Transdermalpatches can be applied directly to the outer layer of the skin. However,the patches only penetrate through the stratum corneum, which is onlyabout 10 μm thick. Thus the vast majority of molecules cannot cross thestratum corneum. There is also a risk of infection due to therequirement for direct contact with the skin.

Other approaches involve the use chemical enhancers and iontophoresis.Another approach is the use of ultrasound. Electroporation, or the useof voltage pulses, has also been used for transdermal delivery.Microneedles are also used in transdermal delivery, consisting of veryshort needles that physically pierce the stratum corneum and therebyallow small molecules to cross the barrier of a patient's skin.Microneedles increase skin permeability by creating micron-sized holesin the skin layer to create an opening for small molecules. However, allof these approaches can irritate the skin and many are too expensive tobe of wide-spread use.

The current approaches to delivery of an agent are therefore inadequateand there remains a need for devices and methods for providing localdelivery of an agent to tissue in a manner that can be easilyadministered, and/or that causes as little skin irritation and pain aspossible.

Methods of fluid delivery for transfecting cells with a range ofmolecules including but not limited to DNA, RNA, plasmids, and proteinsalso suffer from current limitations. Delivery into cells is crucial forgene therapy and for use with CRISPR editing methods. Standardapproaches for introducing materials into cells include: electroporationin which voltage is applied across the cell membrane to create poresthat allow material to enter, use of chemical transfection reagents(such as Lipofectamine) that use liposomal delivery, microinjection, anduse of cell penetrating peptides (CPP).

Most of these methods lead to significant cell death because of shock tothe cell. In several cases, electroporation or chemical transfection isnot compatible with several subsets of cells that are sensitive to theirsurrounding environments and are prone to cell death via standardmethods of delivery. Efficient and non-toxic delivery is especially achallenge for cells that are not in high abundance (such as populationsof T-cells that are isolated from a patient and transected with genesfor CAR-T therapy). In these cases, methods with high toxicity willseverely impact the efficacy of treatment with genetically alteredcells.

Large molecules cannot be locally delivered into cells in patients usingany of these methods. Often, viruses are used to transfect genes intopatient cells, but this approach has limitations and can lead to severaloff-target effects.

There is a need for gentler, more effective, localized approaches todeliver a variety of types of molecules into cell lines for use in avariety of settings, for example as a research tool or in therapeuticsettings. The present disclosure thus provides methods, systems, anddevices for more effective delivery of fluid.

SUMMARY

Various methods and devices are provided for use of a fluid deliverydevice.

In one embodiment, a fluid delivery device is provided that includes ahousing. A fluid vaporizer is disposed within the housing and isconfigured to receive fluid and to produce an aerosol mist of liquidparticles from the fluid. A pump is also provided that is configured toaccelerate the aerosol mist produced by the fluid vaporizer.

The fluid delivery device can vary in a number of ways. For example, thefluid vaporizer can comprise a piezoelectric transducer. In anotherexample, the pump can have an inlet port positioned to disrupt a flowpath of the aerosol mist produced by the fluid vaporizer such that theaerosol mist can be drawn into the pump through the inlet port. The pumpcan also have an outlet port for expelling the aerosol mist therefrom.In still another example, the housing can have an inlet formed thereinfor allowing a fluid to be delivered into the fluid-retaining reservoir.In another example, the pump can be configured to reduce a size of theliquid particles produced by the fluid vaporizer. In still anotherexample, the pump can be configured to reduce a size on average of theliquid particles produced by the fluid vaporizer by a factor of about10. In one embodiment, the housing can have a fluid-retaining reservoir,and the fluid vaporizer can be configured to receive fluid from thereservoir. In another embodiment, the fluid vaporizer and the pump canbe configured to generate an aerosol mist that can pass into up to 1 cmof tissue when an outlet on the housing through which the aerosol mistpasses is positioned about 1 cm away from a tissue surface. Tissue or atissue surface can include cells or a surface containing cells. Inanother example, the aerosol mist can be configured to pass into thetissue or the cells on a timescale of between 1 microsecond and 600seconds. In still another example, the pump can be configured toaccelerate the aerosol mist such that the aerosol mist emerging from thefluid vaporizer is focused over a given delivery radius.

In one embodiment, the device can be configured to deliver fluid intotissue without excising cells of the tissue. In one example, the devicecan include a stopper removably disposed within the inlet in thehousing. In another example, the housing can have an outlet formedtherein and positioned such that the fluid vaporizer can eject theaerosol mist from the housing through the outlet. In still anotherexample, the pump can be configured to draw in and accelerate theaerosol mist after the aerosol mist passes through the outlet in thehousing. In yet another example, the pump can include a fluid inlet portand a fluid outlet port, the fluid inlet and outlet ports beingpositioned adjacent to the outlet in the housing. In still anotherexample, the fluid inlet and outlet ports of the pump can extendsubstantially parallel to one another and can extend transverse to acentral longitudinal axis of the outlet in the housing. In anotherexample, the fluid vaporizer can be disposed between a reservoir and anoutlet formed in the housing.

In one embodiment, the pump can comprise a diaphragm pump. In anotherembodiment, the pump can include an axial fan. In still anotherembodiment, the housing can include an activation switch electronicallycoupled to the fluid vaporizer and/or the pump. In yet anotherembodiment, the activation switch can be configured to simultaneouslyactivate the fluid vaporizer and the pump. In still another embodiment,the housing can include a handle portion configured to be grasped by auser and a body portion having the fluid vaporizer and the pump disposedtherein. In one example, the housing can include a power source forproviding power to the fluid vaporizer and the pump. In another example,the power source can comprise a battery. In still another example, thedevice can include a cartridge removably matable to the housing andconfigured to deliver fluid to the housing. In yet another example, thecartridge can be configured to provide a dosage instruction and/ortiming instructions to the device including a selected pump-speed of thepump and a selected frequency of vibration of the fluid vaporizer forthe fluid. In still another example, the device can be configured to beinoperable unless the cartridge is mated to the housing. In yet anotherexample, the housing can include an activation switch that iselectronically coupled to the fluid vaporizer and the pump and that canbe configured to simultaneously activate the fluid vaporizer and thepump according to the dosage instruction of the cartridge.

In another example, the device can include a controller disposed on thehousing and configured to alter a frequency of the fluid vaporizer and apump-speed of the pump and/or duration of device operation. In anotherexample, the device can include a sensor disposed on the housing andconfigured to determine a distance from the device to a skin of apatient. In yet another example, the device can include a sensorelectronically coupled to a gyroscope and an accelerometer disposed inthe housing and configured to determine an orientation of the device. Instill another example, the device can include a fluid wherein the fluidincludes a drug having a molecular weight of at least about 500 Daltons.In yet another example, the device can include a fluid that includes adrug having a molecular weight of up to about 800 Daltons. In still yetanother example, the device can include a fluid that includes a drughaving a molecular weight of at least about 800 Daltons. In oneembodiment, the device can include a cosmetically acceptable topicalcarrier. In another embodiment, the device can include a fluid thatincludes an oil-water emulsion. In still another embodiment, the devicecan include a fluid that includes at least one of a DNA, protein, virus,phage, bacteria, RNA, mRNA, miRNA, aptamer, stabilized RNA, iRNA, siRNA,chemicals, small molecules, and a plasmid. In yet another embodiment,the device can include a vaporized fluid configured for at least one ofinhalation, oral delivery, ocular delivery, intra-aural delivery, rectaldelivery, and vaginal delivery. In yet another embodiment, the devicecan include a vaporized fluid that can be configured for at least one ofintra-cellular, intra-nuclear, and intra-tissue delivery. In anotherembodiment, the device can include a vaporized fluid that is configuredfor at least one of intra-plant delivery, polymeric delivery, andprotein-structure delivery.

In another aspect, a fluid delivery device is provided that includes ahousing. A fluid vaporizer is disposed within the housing and isconfigured to receive fluid and to produce an aerosol mist of individualnon-coalescing droplets from the fluid by creating an inertia-dominatedfluid regime in the fluid. The device also includes an accelerationsystem disposed within the housing and configured to accelerate theaerosol mist.

The device can vary in a number of ways. For example, the device can beconfigured to eject a vaporized fluid having a Weber number that isequal to or greater than 1, or that is in the range of about 1 to 100,and more preferably that is in the range of about 10 to 50.

In another aspect, a fluid delivery device is provided with a housingwith a fluid-retaining reservoir in the housing. A piezoelectrictransducer is disposed within the housing and is configured to receivefluid from the reservoir and to produce an aerosol mist of liquidparticles from the fluid. The housing has an outlet formed therein thatis positioned such that the piezoelectric transducer can eject theaerosol mist from the housing through the outlet. A pump has an inletand an outlet that are positioned adjacent to the outlet of the housing.The inlet port is configured to draw into the pump the aerosol mistejected from the outlet in the housing, and the outlet port isconfigured to expel the aerosol mist therefrom into a path of theaerosol mist ejected from the housing by the piezoelectric transducer.

In another aspect, a method of producing a mist is provided thatincludes delivering a fluid to a fluid vaporizer that generates a firstmist. The fluid vaporizer delivers the mist to a pump that generates asecond mist from the first mist.

The method of producing a mist can vary in numerous ways. For example,the second mist can have a reduced size relative to the first mist. Inanother example, the fluid vaporizer can comprise a piezoelectrictransducer. In still another example, delivering a fluid to the fluidvaporizer can comprise delivering a fluid to a fluid-retaining reservoirthat is in fluid communication with the fluid vaporizer. In yet anotherexample, the fluid can be delivered to the fluid vaporizer using aremovable cartridge. In still another example, a flow path of the firstmist produced by the fluid vaporizer can be disrupted by an inlet portand an outlet port on the pump. In one embodiment, the second mist canbe ejected from the pump into a flow path of the first mist produced bythe fluid vaporizer. In still another embodiment, the first mist and thesecond mist can be delivered to a skin surface of a patient. In anotherembodiment, the first mist and the second mist can be delivered to cellsin a plate or well. In yet a further embodiment, the method can includeactivating an activation switch electronically coupled to the fluidvaporizer and to the pump to activate the fluid vaporizer and the pump.

In one example, the method can further include positioning an outlet ofeach of the pump and the fluid vaporizer adjacent to a surface, such asa tissue or cells, and a distance from the pump and the fluid vaporizerto a skin of a patient can be detected by a sensor. In still anotherexample, the fluid can comprise a drug having a molecular weight of atleast about 500 Daltons. In another example, the fluid can comprise adrug having a molecular weight of up to about 800 Daltons. In stillanother example, the fluid can comprise a drug having a molecular weightof at least about 800 Daltons. In yet another example, the fluid caninclude cosmetically acceptable topical carriers. In still yet anotherexample, the fluid can include oil-water emulsions. In one embodiment,the fluid can include at least one of a DNA, a protein, a virus, aphage, bacteria, RNA, mRNA, miRNA, an aptamer, stabilized RNA, iRNA,siRNA, and a plasmid suspended in the fluid. In another embodiment,activating a switch on the housing can generate the first mist and thesecond mist configured for at least one of inhalation, oral delivery,ocular delivery, intra-aural delivery, rectal delivery, and vaginaldelivery. In still another embodiment, the pump can reduce a size onaverage of particles of the first mist produced by the fluid vaporizerby a factor of about 10. In yet another embodiment, the method caninclude directing a flow of the first mist and a flow of the second mistat a site selected from an eye, an ear, a wound, a burn, an infection, asurgical site, isolated cells, and a plurality of cells in a section oftissue.

In another aspect, a method for creating a mist is provide that includesintroducing an aerosol in a housing and activating a switch on thehousing such that the housing expels a mist of the aerosol from a firstoutlet in the housing. The mist is then drawn into an inlet of a pump inthe housing and is expelled by a second outlet of the pump into a pathof the mist from the first outlet in the housing such that droplets ofthe mist collide and break apart.

In another aspect, a method for creating a mist is provide that includesintroducing an aerosol into a housing and activating a switch on thehousing such that the housing expels a mist of the aerosol from a firstoutlet in the housing. The mist is then accelerated by a pump within thehousing using an exhaust that emerges from the pump. Droplets in themist collide and break apart and gain acceleration.

BRIEF DESCRIPTION OF DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a side perspective view of one embodiment of a fluid deliverdevice and a cradle;

FIG. 2 is a side perspective, partially exploded view of the fluiddelivery device of FIG. 1 ;

FIG. 3 is another side perspective view of the fluid delivery device ofFIG. 1 ;

FIG. 4 is an exploded perspective view of internal and externalcomponents of the fluid delivery device of FIG. 1 ;

FIG. 5 is another exploded perspective view of the fluid delivery deviceof FIG. 4 from another side;

FIG. 6 is another exploded perspective view of internal components ofthe fluid delivery device of FIG. 1 ;

FIG. 7 is a perspective view of a stopper and reservoir of the fluiddelivery device of FIG. 1 ;

FIG. 8 is a cross-sectional view of the reservoir of FIG. 7 ;

FIG. 9 is a perspective view of a top of a piezo plate of the fluiddelivery device of FIG. 1 ;

FIG. 10 is a perspective view of a bottom of the piezo plate of FIG. 9 ;

FIG. 11 is a perspective view of a pump of the fluid delivery device ofFIG. 1 ;

FIG. 12 is a partially transparent perspective view of the stopper, thereservoir, a piezoelectric transducer, and the pump of the fluiddelivery device of FIG. 1 ;

FIG. 13 is an exploded perspective view of internal and externalcomponents of the fluid delivery device of FIG. 1 ;

FIG. 14 is a cross-sectional view of the fluid delivery device of FIG. 1showing a fluid flow path through the device;

FIG. 15 is an image showing tissue penetration by an aerosol and using afluid delivery device as disclosed herein;

FIG. 16 is a graph showing molecular size capabilities with a topicalapplication as compared to a fluid delivery device as disclosed herein;

FIG. 17 is another graph showing bacterial growth using a fluid deliverydevice as disclosed herein;

FIG. 18 is an image showing fluid droplets created by standardaerosolization as compared to fluid droplets created using a fluiddelivery device as disclosed herein;

FIG. 19 is an image showing disruption of a droplet of food dye sittingin a bath of mineral oil by a commercial aerosol, a topical applicationwith the human hand, and a fluid delivery device as disclosed herein;

FIG. 20 is an image showing distribution of food dye after exiting apiezo versus exiting a fluid delivery device as disclosed herein;

FIG. 21 is an image showing the results of delivering a peptide, NP-6A(780 DA), by a device similar to that disclosed herein into a lesion ina rat model compared to an untreated lesion;

FIG. 22 is a graph showing measured hydration levels after water wasdelivered to 4 subjects through both topical delivery as compared towater delivered using a device similar to that disclosed herein;

FIG. 23 is an image of fluid droplets expelled from a device similar tothat disclosed herein and a standard aerosol;

FIG. 24 is a mass spectrometry trace of a peptide before and after beingpassed through a device similar to that disclosed herein; and

FIG. 25 is an image of an agarose gel showing GFP plasmid and H9C2 cellsinto which GFP plasmid was delivered using a device similar to thatdisclosed herein and compared with a commercially available chemicaltransfection reagent (Lipofectamine 2000).

DETAILED DESCRIPTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Further, in the present disclosure, like-named components of theembodiments generally have similar features, and thus within aparticular embodiment each feature of each like-named component is notnecessarily fully elaborated upon. Additionally, to the extent thatlinear or circular dimensions are used in the description of thedisclosed systems, devices, and methods, such dimensions are notintended to limit the types of shapes that can be used in conjunctionwith such systems, devices, and methods. A person skilled in the artwill recognize that an equivalent to such linear and circular dimensionscan easily be determined for any geometric shape. Sizes and shapes ofthe systems and devices, and the components thereof, can depend at leaston the anatomy of the subject in which the systems and devices will beused, the size and shape of components with which the systems anddevices will be used, and the methods and procedures in which thesystems and devices will be used.

In general, methods and devices are provided for generating a fluid miststream that is capable of penetrating into tissue or into cells whileminimizing any tissue irritation and/or pain and without the need fordirect contact between the device and the tissue or the cells. In anexemplary embodiment, the methods and devices are used for transdermalfluid delivery, however the methods and devices can be utilized insurgical approaches to apply a fluid to tissue intracorporeally.

In an exemplary embodiment, a fluid delivery device is provided having ahousing with a fluid-retaining reservoir, a piezoelectric transducerdisposed within the housing and configured to receive fluid from thereservoir and to produce an aerosol mist of deformable liquid particlesfrom the fluid, and a pump configured to pump the aerosol mist producedby the piezoelectric transducer therethrough. A handle of the housingcan have a trigger that can be activated to cause fluid flow through thedevice. The handle can be sized to allow a user to grasp the handle inone hand while simultaneously operating the trigger with a finger onthat same hand. A power source, such as a replaceable battery, may belocated in the interior of the handle, or the handle can include a plugor cord, or any combination of the two, for connecting to an externalpower source. The power source can also be located in the body of thedevice. A body of the housing can have an inlet and an outlet. The inletcan be configured to receive fluid from a fluid supply device, such as asyringe or cartridge. The inlet may be upstream of the reservoir and thepiezoelectric transducer. The outlet can be configured to provide apassage through which fluid can exit the device. The outlet can bepositioned adjacent to the pump. In an exemplary embodiment, fluidexpelled from the outlet can be drawn into the pump and then expelledfrom the pump. The particular arrangement of the outlet and the pump hasbeen found to create a fluid stream that is effect to penetrate intotissue without excising the tissue cells or across the cell membrane forentry into cells. Due to the deep penetration, the fluid will remainwithin the tissue for longer periods as compared to prior art methods.The particular arrangement has also been found to allow for the deliveryof molecules having a much larger size as compared to prior art fluiddelivery devices. The particular arrangement is additionally capable ofdelivering large molecules (such as plasmids) into cells.

FIGS. 1-4 illustrate one embodiment of a device 1 that generallyincludes a housing 10 having a handle 11 and a body 12 extending fromthe handle. The illustrated housing 10 is formed from two pieces, a top10 t and a bottom 10 b (as seen in FIG. 4 ), that mate together to formthe housing 10 and that define an interior cavity within the housing.The housing 10 includes a handle portion 11 for grasping and a bodyportion 12 extending from the handle 11. The housing 10 can be made ofany rigid material, such as plastic or metal. The illustrated housing 10is shown seated within a cradle 15. While the cradle 15 is illustratedas a receiving base into which the housing 10 is placed, one skilled inthe art will appreciate that the cradle 15 can be any structure that iscapable of seating the housing 10. For example, the cradle 15 can be avertical structure, a structure attached to other devices or equipment,and/or a structure securable to a user (such as a structure securable toa belt). The cradle 15 may also include other features, such as featuresfor securing the housing 10 in place. These can include, for instance,clips, clamps, magnetic holdings, straps, or any other securingmechanism operable with the housing 10. The cradle 15 can furtherinclude charging or power mechanisms operable to provide power to thehousing 10 or to a power source within the housing 10. For example, thecradle 15 can include cables, wires, coils, or any other mechanism forproviding power or charging to the device. The cradle 15 can be made ofany rigid or soft material, such as plastic, metal, or cloth capable ofretaining the housing 10. In other embodiments, the housing can bedesigned to be free-standing without the use of a cradle.

The handle 11 of the illustrated housing 10 has a proximal end 11 p anda distal end 11 d. While the handle 11 is generally cylindrical andelongate in shape, the handle 11 can have any shape or size that wouldallow a user to grasp the handle in one hand, such as a pistol grip, apencil grip, a scissor, grip, or any other configuration. As furthershown, the handle 11 includes a trigger 13. The illustrated trigger 13is located on the housing bottom surface of the bottom 10 b, however thetrigger 13 can be positioned at any location on the device 1, forexample on the top or bottom of the handle 11 or the top or bottom ofthe body 12, or on any side surface thereof. Activation of the trigger13 is effective to activate a pump 40 and a piezoelectric transducer 30within the house, while release of the trigger 13 will terminate use ofthe pump 40 and the piezoelectric transducer 30. While the illustratedtrigger 13 activates the pump 40 and piezoelectric transducer 30, oneskilled in the art will appreciate that activation of the trigger 13 maycause a variety of different functions and/or processes of the device toactivate. For example, activation of the trigger can cause activation ofthe pump and/or the piezoelectric transducer at selectable pump-speedsand/or frequencies of vibration and voltages, respectively. Theillustrated trigger 13 includes a button cover 13 c, a button bracket 13b, and a switch 13 s electrically coupled to a circuit board 50 withinhousing 10 (as seen in FIGS. 4 and 6 ). However, the trigger 13 may beany type of switch capable of being electrically coupled to the circuitboard 50, such as a dial, a slide, a lever, a knob, a button, a touchscreen, or a touch panel. The trigger 13 can also be any type of sensor,such as a distance sensor or a pressure sensor that can be automaticallyactivating if the device is within a certain distance or pressed againsta barrier (for example a patient's skin).

Within the proximal end 11 p of the handle 11, a power source 17 iselectrically coupled to the circuit board 50 (as seen in FIG. 4 ). Thepower source 17 is shown as a replaceable battery 17 b with a batteryconnector 17 c (as seen in FIG. 6 ). However, the power source 17 may beanything that is configured to supply power to the device. For example,the power source 17 may be a rechargeable battery or a cord extendingfrom the proximal end 11 p of the handle and configured to plug into anoutlet or power source. The power source 17 may be replaceable by auser. For example, the top and bottom 10 t, 10 b of the housing 10 canbe separable as shown in FIG. 4 , or the proximal end 11 p of the handlecan include a removable battery cover (not shown) to provide access tothe power source 17.

As shown in FIG. 2 , the body 12 of the housing has an inlet 18 forallowing fluid to be delivered into the housing 10. The illustratedinlet 18 has a stopper 14 seated therein, with the stopper removed theinlet 18 can be configured to receive a cartridge 21. The inlet 18receives fluid added to the device, and the fluid may be expelled froman outlet 16 in the housing 10, as seen in FIG. 3 . The illustratedinlet 18 is shaped as a cylindrical channel with a diameter ofapproximately 0.1 mm to approximately 10 cm. For example, the diametercan be approximately 1.5 mm. However, one skilled in the art willappreciate that the inlet 18 may be sized and/or shaped in any formnecessary to receive fluid, as well as to seat the stopper 14 and/or thecartridge 21. Other shapes include, by way of non-limiting example, acuboid receiving channel, a receiving slot, or a receiving tray. Theillustrated outlet 16 is also shaped as a cylindrical channel with adiameter of approximately 0.1 mm to approximately 10 cm. For example,the diameter can be approximately 1.5 mm. Again however, one skilled inthe art will appreciate that the outlet 16 may be sized and/or shaped inany form necessary to allow the expulsion of fluid. While the stopper 14shown in FIG. 2 has a head and a plug, the stopper may also take anyform that will fluidly seal the inlet 18, such as a cork, a snap-oncover, or a cap.

The cartridge 21 can contain fluid to be introduced into the inlet 18and to subsequently flow downstream to a reservoir 20 (as seen in FIG. 4). The cartridge 21 may contain one type of fluid or multiple types offluid separated by a variety of mechanisms, such as physical barriers orimmiscible barriers (for example an oil phase). The cartridge 21 mayalso contain electrical components that may interact with the device 1.For example, the cartridge 21 can include an electrical component thatmay directly or wirelessly interact with the circuit board 50 andprovide a signal to the circuit board 50 containing instructions and/ordetails on fluid type, dosage information, dispersal rates, dispersaltimes, or any other details related to the fluid contained within thecartridge 21. The cartridge 21 may also contain electrical, physical, orfluid components within the cartridge 21 itself that self-regulate theintroduction of fluid from the cartridge 21 to the inlet 18 and/or thereservoir 20. For example, the cartridge 21 may be shaped or sizedspecifically to allow a particular fluid flow rate. Additionally,multiple cartridges 21 may be used together to provide a fluidcombination to be introduced to the device. The illustrated cartridge 21also has a sealed port 22 that prevents fluid flow from the cartridge 21until insertion into the inlet 18. For example, the sealed port 22 canhave a rubber or plastic seal that is punctured by the inlet 18 uponinsertion. As another example, the sealed port 22 may have an electricalcomponent that senses insertion into the inlet 18 and allows fluid flowupon activation of the device. While the cartridge 21 is illustrated ashaving a cylindrical shape, any shape capable of retaining fluid andbeing introduced into the inlet 18 can be used, such as a flexible pouchor a cuboidal structure. Additionally, the cartridge 21 can be made ofany material capable of retaining fluid, for example rigid or flexibleplastic or glass.

The illustrated device further includes a reservoir that is in fluidcommunication with the inlet. The reservoir can be a fluid retainingchamber within the housing of the device capable of receiving fluidadded to the device through the inlet. The reservoir is downstream ofthe inlet and cartridge and upstream of a piezoelectric transducer.While a reservoir is shown, the device need not include a reservoir andinstead the cartridge can form the reservoir. The cartridge canintroduce fluid directly into the fluid stream of the device to thepiezoelectric transducer.

In other embodiments, the device or a portion thereof can be designedfor one-time use and/or can be disposable. Fluid can be introducedduring use and/or immediately preceding use into the reservoir, into apart of the device containing the reservoir, and/or into port(s) and/orchannel(s) leading to the fluid stream of the device.

As seen in FIGS. 7 and 8 , the reservoir 20 is in the form of asubstantially L-shaped cylindrical shaped chamber with a substantially90° angled turn leading to the piezoelectric transducer 30. As will beappreciated by one skilled in the art, however, the reservoir 20 canhave any shape and/or volume capable of retaining fluid, such as acuboidal structure. The volume of the reservoir can also vary, and inone embodiment could be between approximately 1 μl and 500 ml.

As indicated above, the piezoelectric transducer is located downstreamof the reservoir and upstream of the outlet in the housing. Thepiezoelectric transducer is in fluid communication with the reservoirsuch that fluid flows from the reservoir to the piezoelectric transducerby gravitational forces or by any other method capable of causing fluidflow, such as through use of a pump, capillary action, electromagneticforces, vacuum suction, electrophoresis, a wick, or electro-osmoticflow. Upon contact, the piezoelectric transducer is configured to causethe fluid to separate into fluid droplets in the form of an aerosol mistof liquid particles. The fluid droplets may collide with and separatefrom one another within the piezoelectric transducer, further reducingdroplet size. Upon expulsion from the piezoelectric transducer, thefluid droplets will flow in a transitional flow regime (between laminarand turbulent flow) or a turbulent flow regime that may cause rapiddroplet coalescence and/or further droplet breakup, depending on avariety of factors such as the fluid, any exit conditions, a directionof spray, and the frequency of vibration with which the fluid dropletsare generated in the piezoelectric transducer. A laminar flow regime isa flow regime characterized by flows in parallel layers with nodisruption between the layers, and a turbulent flow regime is a flowregime characterized by chaotic property changes. While the device isdescribed in connection with a piezoelectric transducer, one skilled inthe art will appreciate that any component may be used that isconfigured to cause separation of the fluid into droplets to create anaerosol mist, such as a metal, ceramic, or conductive diaphragm.

As illustrated in FIGS. 4-6 , the piezoelectric transducer 30 isprovided downstream from the reservoir 20 and upstream from the outlet16. The piezoelectric transducer 30 is coupled to the reservoir 20 byscrews 32 and passage between the two is sealed with an O-ring 33. Thepiezoelectric transducer 30 has a piezo plate 31, shown in more detailin FIGS. 9 and 10 , that is capable of being vibrated and/or oscillatedat ultrasonic frequencies to drive the separation of the fluid intodroplets and to produce an aerosol mist of liquid particles from thefluid. The transducer can be manufactured, for example, by Homidics.However other transducers can be used.

The piezoelectric transducer 30 is electrically coupled to the circuitboard 50 and may be activated upon activation of the trigger 13. Afrequency of vibration of the piezo plate 31 may be varied to causegreater separation or less separation of the fluid. The frequency ofvibration of the piezo plate can vary between 1 kHz and 10 mHz, forexample. A voltage applied to the piezoelectric transducer 30 may alsobe varied. While the voltage can vary depending on the piezoelectrictransducer, the voltage may be between −30 and 30 V, for example. Thefrequency of vibration and/or voltage may be varied manually orautomatically. For example, the frequency and/or voltage may be variedmanually through use of a controller (not shown) either directly orwirelessly coupled to the circuit board 50 and capable of sending asignal to the control board 50 or automatically based on a signal fromthe cartridge 21. The controller can take any form necessary to providecontrol over the frequency of vibration, such as a dial, a knob, apanel, or a series of buttons positioned on the housing 10 or separatelyfrom the housing 10. The controller can also include pre-set programsfor controlling the device 1 or timing delivery.

The piezoelectric transducer 30 expels fluid droplets from the piezoplate 31 and through the outlet 16. A size of streams of the fluiddroplets generated by the piezoelectric transducer will vary dependingon the fluid and the piezoelectric transducer. For example, the streamsmay be microstreams with volumes ranging from approximately 1 μl toapproximately 10 ml. While the piezoelectric transducer 30 herein expelsfluid droplets through the outlet 16, the piezoelectric transducer 30can also expel fluid droplets to within the housing 10. The directionand/or force of expulsion and/or size of the fluid drops may be varied,for example by varying the frequency of vibration and/or voltage.

Upon expulsion from the housing, the fluid droplets may interact with apump or a similar component that provides the ability to pressurizeand/or break up the fluid droplets by putting the droplets into atransitional flow regime or into a turbulent flow regime. The pump canbe placed within the housing of the device. However, the pump may beplaced anywhere as long as it can interact with the fluid droplets. Thepump can have a pump inlet and a pump outlet. The pump inlet may bepositioned to interact with the fluid flowing from the outlet in thehousing. The pump inlet may draw the fluid droplets into the pump. Anamount of the fluid in a range of about 10-90% of the fluid can be drawninto the pump, and the force of the pump can accelerate the aerosol thatis not drawn into it directly via the exhaust stream. The fluid dropletscan be accelerated through a pumping action of the pump and/or anexhaust stream of the pump. The pump can further increase accelerationand reduce the size of the fluid droplets by, for example, drawingdroplets through the fluid path of the pump and by, for example, exhaustof the pump. For example, the fluid droplets within the pump can beaccelerated to a greater speed and may continue to collide with oneanother, further reducing droplet size. The pump can then expel thefluid droplets through the pump outlet. The pump outlet can bepositioned such that the expelled fluid droplets from the pump interactwith the fluid droplets expelled from the outlet of the housing. The twoexpelled fluid droplet streams can influence, collide, cross, interact,and/or disrupt each other. This interaction can cause the fluid dropletsto further reduce in size and give them more velocity. This interactioncan also generate a transitional flow that has properties of both alaminar flow and a turbulent flow. The fluid droplets can accelerateaway from the pump and impact tissue of a patient or a membrane of acell. This impact can also further reduce droplet size. As a result, thefluid droplets are capable of passing through the tissue. The fluiddroplets can retain their native function as they pass through thetissue, thus administering the functional fluid droplets deep within apatient's tissue. Using both the piezoelectric transducer and the pumpin combination can allow the fluid droplets to be significantly reducedin size, for example by a factor of about 10 or more, and accelerated ata high speed as the fluid droplets impact the tissue.

In some embodiments a fan, such as an axial fan (not shown), can be usedin place of or in addition to the pump to generate turbulent flow. Forexample, the fan can be placed downstream of the pump so that fluiddroplets exiting the pump can be drawn into the fan to create anadditional turbulent environment and allow additional collisions betweenthe fluid droplets prior to reaching the tissue. One skilled in the artwill recognize that other such fluid disrupting elements could be usedin place of or in addition to the pump to reduce fluid droplet size uponcollision and to encourage further focusing of fluid mist that emerges.

As illustrated in FIGS. 11 and 12 , the pump 40 is placed adjacent tothe piezoelectric transducer 30. The pump 40 is in the form of a housinghaving an inner cavity formed therein. With reference to FIG. 6 , a pumpvibration jacket 43 can be disposed around the housing to reducevibration of the pump 40. As further shown in FIGS. 11 and 12 , the pump40 includes a pump inlet 41 and a pump outlet 42 that are in fluidcommunication with the cavity in the pump 40, and that are positioned toinfluence the flow of fluid droplets from the piezo plate 31 and theoutlet 16 of the housing 10. In particular, the illustrated pump inletand pump outlet 41, 42 are positioned a distance apart from one anotherand have central axes that extend substantially parallel to one another.The pump inlet and pump outlet 41, 42 each extend from the pump 40 intothe path of fluid flow exiting from the outlet 16 in the housing 10. Thepump inlet and pump outlet 41, 42 together form an angle that is lessthan 90° with an axis of the outlet 16 of the housing 10, as illustratedin FIG. 12 . In various embodiments, the angle between the pump inletand pump outlet 41, 42 and the axis of the outlet 16 of the housing 10can vary, for example between approximately 60° and approximately 90°,as long as the pump inlet and pump outlet 41, 42 can influence the flowof fluid droplets from the piezo plate 31 and the outlet 16 of thehousing 10.

The configuration of the pump inlet and pump outlet 41, 42 can vary. Inthe illustrated embodiment, the pump inlet 41 is shaped as a cylindricalchannel. In one embodiment, the pump inlet 41 has an inner diameter thatis approximately 0.1 mm to approximately 10 cm. For example, thediameter can be approximately 1.5 mm. One skilled in the art willappreciate that the pump inlet 41 can be sized and/or shaped in any formnecessary to operate with the pump and draw in fluid droplets. Theillustrated pump outlet 42 is also shaped as a cylindrical channel, andthe pump outlet 42 can likewise have a diameter that varies. In oneembodiment, the diameter can be approximately 0.1 mm to approximately 10cm. For example, the diameter can be approximately 1.5 mm. As with thepump inlet 41, the pump outlet 42 may vary in size and/or shapedepending on the pump and the amount of fluid to be expelled.

The pump 40 can also have a variety of configurations to facilitate theflow of fluid therethrough. As shown in FIG. 11 , the illustrated pump40 is a pneumatic diaphragm pump. One non-limiting example of adiaphragm pump is the 3013VD/0,7/E/DC diaphragm pump provided by Thomasby Gardner Denver. In use, fluid droplets are accelerated within thepump 40. Altering a pump speed and/or a pressure of the pump 40 caninfluence the speed and/or size and/or expulsion direction of the fluiddroplets. One skilled in the art will appreciate that the pump 40 may beany pump capable of reducing the size of fluid droplets and/orinfluencing the flow of fluid droplets from the piezoelectric transducerand/or the outlet of the housing, such as a rotary vane pump or apositive displacement pump.

The pump 40 is electrically coupled to the circuit board 50 and may beactivated upon activation of the trigger 13. The pump speed and/or pumppressure may be varied manually or automatically. For example, the speedand/or pressure may be varied manually through use of a controller (notshown) either directly or wirelessly coupled to the circuit board 50 andcapable of sending a signal to the control board 50 or automaticallybased on a signal from the cartridge 21. The controller can be the samecontroller for the piezoelectric transducer 30 or it can be a separatecontroller. The controller can take any form necessary to providecontrol over the pump speed and/or pump pressure, such as a dial, aknob, a panel, or a series of buttons positioned on the housing 10 orseparately from the housing 10.

As indicated above, in use the pump 40 expels fluid droplets from thepump outlet 42. The direction and/or force of expulsion of the fluiddroplets may be varied, for example by varying the pump speed and/orpump pressure. The fluid droplets will flow back into the spray outputflowing from the outlet 16 in the housing, and the fluid spray outputwill pass through the tissue of the patient or into cells for deliveryor transfection of molecules. The fluid may consist of any fluid withany molecular weight. It has been found that the combination of thepiezoelectric transducer and the pump are effective to create a mist orstream of fluid having a size that will pass into tissue to a depth of,for example, 1 cm or deeper. As a result, fluid having a highermolecular weight can be utilized and will still penetrate into thetissue. In an exemplary embodiment, the fluid has a molecular weight ofabout 500 Daltons or greater. The molecular weight of the fluid may alsobe between about 500 Daltons and about 800 Daltons. The molecular weightmay also be greater than 800 Daltons or less than 500 Daltons. Afterpassing through the device 1, the resulting fluid droplets will be inthe sub-micron range and can penetrate through skin pores (approximately3 μm). A velocity and a width of a flow stream of the fluid dropletsafter expulsion may vary depending on the fluid used and thepiezoelectric transducer and the pump and the size of the outlet, whichcan vary from about 0.1 to 5 cm in diameter. But the velocity may be,for example, 0.1 to 0.2 liters/sec, and the width of the spray outputmay be for example about 1 cm.

In certain exemplary embodiments, the fluid is a medicament used fortreating wounds. For example, the fluid can be any antibiotic, forexample an antibiotic to treat a skin and soft tissue infection such asceftaroline. The functionality of the fluid, such as an antibiotic likeceftaroline, can be maintained as the fluid is converted into the fluiddroplets and passed through the tissue of the patient. Additionally,while the device 1 can be used for a variety of transdermal deliverypurposes, such as to treat skin and soft tissue infections, one skilledin the art will appreciate that fluid may be delivered to internal bodytissue, e.g., via open surgical techniques, endoscopic techniques, orlaparoscopic techniques. In other embodiments the device can beconfigured to delivery fluid intranasally. In various embodiments, thefluid can be a vaporized fluid configured for at least one ofinhalation, oral delivery, ocular delivery, intra-aural delivery, rectaldelivery, and vaginal delivery. The vaporized fluid can be configuredfor at least one of delivery into ears or eyes. The vaporized fluid canbe delivered onto a plate, well, or other surface containing cellsand/or cell layers and/or tissue layers and/or plant cell layers fordelivery.

The fluid can be a cosmetically acceptable topical carrier. For example,the cosmetically acceptable topical carrier can include an ingredientselected from one or more of the following five classes: wetting agents,emulsifiers, emollients, humectants, and fragrances. In certainembodiments, the cosmetically acceptable topical carrier includesingredients from two or more of the above-mentioned classes, such asingredients from at least three or more of such classes. In someembodiments, the cosmetically acceptable topical carrier includes water,an emulsifier, and an emollient. Cosmetically acceptable topicalcarriers can also be solutions, suspensions, emulsions such asmicroemulsions and nanoemulsions, gels, solids and liposomes.

In some embodiments, the fluid can include an oil-water emulsion. Thefluid can also include at least one of a DNA, protein, virus, phage,bacteria, RNA, mRNA, miRNA, aptamer, stabilized RNA, iRNA, siRNA, and aplasmid. The device and the fluid can also be configured to be used inCRISPR operations and/or applications, such as in gene editing and/orgene delivery.

As indicated above, the device 1 includes a circuit board. The circuitboard can be coupled to the power source, the trigger, the pump, thecartridge, and/or the piezoelectric transducer. The circuit board caninteract with the power source, the switch, the pump, the cartridge,and/or the piezoelectric transducer either directly or wirelessly. Forexample, the circuit board can be electrically coupled to the powersource and can provide power to the pump and the piezoelectrictransducer. The circuit board can receive signal(s) from the trigger,for example indicating actuation of the trigger by a user. The circuitboard can send and receive signal(s) to and from the pump and thepiezoelectric transducer. For example, the circuit board can sendsignals activating and/or deactivating the piezoelectric transducer andthe pump. The circuit board can also send and receive signals regardingthe functionality or condition of the piezoelectric transducer and thepump, such as the frequency of vibration and/or the voltage of thepiezoelectric transducer and the pump speed and/or the pressure of thepump. The circuit board can additionally send signal(s) to and/orreceive signal(s) from the cartridge, for example pertaining toinstructions and details on fluid type, dosage information, dispersalrates, and dispersal times. The circuit board can then send signal(s) toand/or receive signal(s) from the pump and/or the piezoelectrictransducer regarding the signal(s) sent to and/or received from thecartridge. Insertion of the cartridge and/or activation of the triggermay prompt signals from and/or to the circuit board, the pump, and/orthe piezoelectric transducer. The circuit board may additionally sendsignals to and/or receive signals from a controller (not shown), forexample relating to the operation and condition of the device. Thecontroller may be the same controller or a different controller as thecontrollers that may control the functionality of the pump and thepiezoelectric transducer. The circuit board can send signals or receivesignals using integrated wireless technologies to external instrumentsor operators for adjustment of the dosage, the pump speed, the frequencyof vibration and/or the voltage of the piezoelectric transducer, or forany other aspect of device operation with real time feedback.

As illustrated in FIGS. 4-6 , the circuit board 50 is coupled betweenthe power source 17 on the board's proximal end 50 p and thepiezoelectric transducer 30 and the pump 40 on the board's distal end 50d, with the trigger 13 coupled therebetween. However, one skilled in theart will appreciate that the circuit board 50 may be placed at anylocation within or on the housing 10 wherein the circuit board 50 can becoupled to the power source 17, the piezoelectric transducer 30, and thepump 40. Activation of the trigger 13 will cause the circuit board 50 toactivate the piezoelectric transducer 30 and the pump 40, anddeactivation of the trigger 13 will cause the circuit board 50 todeactivate the piezoelectric transducer 30 and the pump 40.

In some embodiments, activation of the trigger 13 can cause apre-programmed response from the circuit board 50. For example, thecartridge 21 can be inserted into the device. Upon insertion, thecartridge 21 can send an instruction signal to the circuit board 50containing dosage instructions regarding the fluid contained in thecartridge 21. Based on the instruction signal, the circuit board 50 cansend signals to the pump 40 and the piezoelectric transducer 30providing the appropriate pump-speed and frequency of vibration for thefluid to be administered. Upon activation of the trigger 13, the circuitboard 50 can cause administration of the fluid according to the providedinstruction signal. The circuit board 50 can also be configured toactivate either just the piezoelectric transducer 30 or just the pump40.

Additionally, the device may be further provided with sensors fordetecting motion and/or orientation and/or distance of the device fromtissue or other entity (such as cells on a plate or in wells). Thesensors can send signals directly and/or wirelessly to the circuit boardand/or a controller (not shown). The circuit board and/or controller maythen alter functionality of the device based on the received signal(s).For example as illustrated in FIG. 13 , a gyroscope 60 and anaccelerometer 61 may be provided within or on the housing 10 for sendingorientation signal(s) to the circuit board 50 and/or a separatecontroller to allow determination of an orientation of the device. Thegyroscope 60 and the accelerometer 61 may be located anywhere within oron the housing 10. The circuit board 50 and/or controller may receiveand use the orientation signal(s) by, for example, deactivating thedevice until the device is in a proper orientation for delivery of afluid or altering the flow rate, pump-speed, and frequency of vibrationbased on the orientation of the device.

As another example, the device may include a distance sensor 62positioned anywhere on the housing 10. The distance sensor may detectthe distance of the device from a tissue of a patient and may send adistance signal(s) to the circuit board 50 and/or the controller. Thecircuit board 50 and/or controller may receive and use the distancesignal(s) by deactivating the device until the device is within a properrange for delivery of a fluid. The distance sensor(s) can also beconfigured to interact with the cartridge.

Further components may be added to the device, such as a fan 63 coupledanywhere on the housing 10 and capable of drying tissue before, during,and/or after administration of the fluid drops. A cooling and/or heatingsystem 64 may be provided within and/or on the housing 10 capable ofheating and/or cooling the fluid and/or the tissue of the patient.

Ultraviolet (UV) light, white light, or a halogen may be provided to gelthe fluid droplets after being expelled from the piezoelectrictransducer 30, after being expelled from the pump 40, and/or after beingexpelled from the outlet 16. For example, a shutter and UV LED 65 can becoupled to the circuit board 50 and can expose the fluid droplets to UVlight for variable durations as the fluid droplets are expelled from thepump 40 (as shown in FIG. 13 ). The shutter and UV LED may be placedanywhere within or on the housing 10. In another example, LED lights canbe included to illuminate a target delivery site. Additionally, bluelight or red light can be added for various purposes includingincreasing blood circulation to the site or for antibacterial use.

A controller for delivering electrical currents and/or acoustic and/orultrasonic waves 66 may be coupled to the circuit board 50, positionedon the housing 10, and configured to pass current and/or waves from thedevice to the tissue of the patient to increase permeability. Thecontroller can also include a timing feature, such as a timer thatcontrols duration, pattern, length, etc. of delivery from the device,for example a timer for delivery over a given time period.

A camera 67 may be coupled to the circuit board 50 and placed anywhereon the housing 10 to allow a user to monitor a tissue treatment site andensure a desired location on the tissue of the patient was treated whiletreatment is ongoing. The camera 67 can be configured to wirelesslytransmit information to an external operator or device.

In use, as illustrated in FIG. 14 , a fluid is introduced into thereservoir 20 inside the housing 10. The fluid flows from the reservoir20 and against the piezoelectric transducer 30 and piezo plate 31. Theoutlet 16 of the housing 10 may be positioned within a certain distanceof a tissue 70 of a patient, and the device 1 need not contact tissue.The outlet 16 is also positioned to cause fluid to flow across the inlet41 and the outlet 42 of the pump 40. Activating the switch 13 can causethe piezoelectric transducer 30 and/or the pump 40 to activate and cancause the fluid to be expelled as fluid droplets from the outlet 16 ofthe housing 10. The fluid expelled from the outlet 16 of the housing 10will be drawn into the inlet 41 of the pump 40 and expelled from theoutlet 42 into a path of the fluid droplets from the outlet 16 of thehousing 10, causing the expelled fluid droplets to collide and furtherbreak apart. The fluid will penetrate into the tissue 70 of a patient,and due to the size of the particles the fluid can penetrate into thetissue by a depth of at least about 1 cm. The tissue 70 is used hereinas an example delivery target, but a variety of delivery targets can beused, such as a layer of cells.

Provided herein are example test results, including real-world dataobtained using a device as disclosed herein. The following examplesshould be considered to be illustrative and in no way limiting to theinvention.

EXAMPLE TEST RESULTS #1

A device having a configuration as disclosed in FIGS. 1-14 was used in atest along with a standard aerosol generated using only thepiezoelectric transducer to compare dye penetration between the deviceand the aerosol. A mix of water and brilliant blue dye with a molecularweight of 792 Daltons was used to test penetration. Both the aerosol andthe device were held 1 cm away from skin, and the solution was sprayedonto chicken and porcine skin-covered tissue. The skin and tissue werecut and dye penetration was measured. It was shown that the spray fromthe aerosol did not penetrate either animal skin to any noticeabledepth. However, using the device, a uniform penetration was observed toa depth of 1 cm for the porcine tissue and a depth of 1.23 cm for thechicken tissue, as shown in FIG. 15 . These results show that drugs witha molecular weight of over 500 Daltons can be penetrated through skinand soft tissue using device. In between a range of 500 to 800 Daltons,there are a number of antibiotics, such as those used to treat skin andsoft tissue infections. One example is ceftaroline, which is anantibiotic for Methicillin-resistant Staphylococcus aureus. As shown inFIG. 16 , the molecular size of ceftaroline falls below the molecularsize of the blue dye, while the topical aerosol is largely limited inits ability to deliver molecules with a molecular size greater than 500Daltons to any noticeable depth. Thus the device can be successful atdelivering ceftaroline to a significant depth within a tissue of apatient. In addition, although this test achieved penetration of largemolecules deeper than 1 cm into tissue, this required depth can varybased on the nature of a skin condition or region of the body targeted.The method of delivery therefore can be designed to optimize depth ofdelivery based on clinical requirements.

EXAMPLE TEST RESULTS #2

In a further example, it was shown that antibiotics passing through adevice having a configuration as disclosed in FIGS. 1-14 retained theirnative function against bacteria, as shown in FIG. 17 . Inhibition ofbacterial strain E. Coli DH5-α with antibiotics dissolved in deionizedwater was tested by passing the antibiotics and water through thedevice. The three antibiotics tested were azithromycin (5 mg/mL),vancomycin (15 mg/mL), and streptomycin (20 mg/mL). As a positivecontrol, the same antibiotics (not passed through the device) weretested. Additional controls included deionized water, and deionizedwater passed through the device. After addition of 100 μl of antibioticsor deionized water into 8 mL of LB broth, 100 μl of bacterial stock at0.5 OD at 600 nm was added. The experiment was performed with 4biological replicates and 3 technical replicates, providing a samplesize of n=12. Samples were incubated at 37° centigrade and 200 RPM in ashaker for 6 hours and then optical density was measured at 600 nm in aspectrophotometer. All antibiotics retained their native function afterbeing passed through the device, and there was no decrease in bacterialinhibition due to passing through the device. Deionized water passedthrough the device had no antibacterial effects, indicating that thedevice itself does not induce bacterial inhibition. FIG. 17 shows thedata for azithromycin with final ODs normalized relative to startingpoint ODs to display amount of growth over the time. Similarly,vancomycin and streptomycin retained their native function after beingpassed through the device.

EXAMPLE TEST RESULTS #3

In yet another experiment, the ability of a device having aconfiguration as disclosed in FIGS. 1-14 to enable deep penetration incomparison to a standard aerosol was explored. Water was fed into thereservoir of the device and collected either after standardaerosolization by the piezoelectric transducer alone or after passingthrough the device 1 with the pump in a bath containing light mineraloil (Sigma) with 1.5% (v/v) Span-80 (Sigma) as a stabilizer that wouldprevent droplet coalescence upon contact. The emulsions were thenpipetted onto a coverglass and observed using brightfield microscopyunder 4× magnification. As shown in FIG. 18 , fluid droplets passedthrough the device with the pump were on average smaller by a factor often than those produced using standard aerosolization.

EXAMPLE TEST RESULTS #4

In another experiment, the ability of a device having a configuration asdisclosed in FIGS. 1-14 to perform transdermal drug delivery wascompared to a commercial aerosol designed to treat minor skin wounds andtopical application with the human hand (such as in applying a lotion).The delivery methods were used to “disrupt” a droplet of food dyesitting in a bath of mineral oil. As is illustrated in FIG. 19 , theonly delivery method that left the droplet intact was the device whilethe commercial aerosol and spreading with hands distributed the food dyewidely. In a similar experiment, the distribution of food dye wascompared after exiting a piezo versus exiting the device. As illustratedin FIG. 20 , the piezo led to uneven distribution while the deviceprovided an even and more concentrated distribution over the areaadministered. The results of both studies suggest that the deviceprovides significantly less force than existing approaches totransdermal delivery while being more even and uniform, suggesting thatthe device is well suited for transdermal drug delivery because thedevice is low pressure and causes little or no skin damage.

EXAMPLE TEST RESULTS #5

Another experiment was conducted to examine the results of delivering awound-healing peptide. As illustrated in FIG. 21 , a wound healingpeptide, NP-6A (780 DA) was delivered by a device having a configurationas disclosed in FIGS. 1-14 into a lesion in a diabetic (ZDF) rat model.The peptide (in sterile saline) was delivered through the device at aconcentration of 300 nM daily for 5 days. As visible in FIG. 21 , thewound treated with the peptide showed much greater healing than theuntreated wound, illustrating that functionality of the peptide wasretained even after being delivered through the device. The experimentwas repeated in healthy lean female rats (Zucker Lean) with astandardized skin punch where a 43% improvement was seen in rats treatedwith a peptide therapeutic delivered through the device. After 4 days oftreatment, the untreated wound was an average of about 19.16 mm² inwound size (2.00 mm² STD) compared to an average of about 11.36 mm²wound size (2.77 mm2 STD) in rats treated with the peptide NP-6Adelivered through the device. The results of the studies show thatpeptide drugs delivered through the device retain their pharmacologicalfunctionality, delivery through the device causes no or very minimalskin disruption, which is crucial for treatment exemption, and thatlarge drugs can be effectively delivered into skin through the device,for example by safely delivering large peptides into wounds.

EXAMPLE TEST RESULTS #6

In yet another experiment, 4 human subjects volunteered to have about 50μL of sterile distilled water sprayed into their hand and have hydrationlevels measured with a Corneometer CM825 device. Skin was visuallyinspected for any discoloration at the time of study and after 24 hours,and subject comfort was assessed and self-reported. A pen was used todraw circles denoting a delivery site (having a circle diameter of about1.5 cm) on the backs of the right and left hands. Hydration in thecircled regions for both the right and left hands was assessed at thestart with a Corneometer CM 825. A device having a configuration asdisclosed in FIGS. 1-14 was used for about 30 seconds to deliver about50 μL sterile water to the left hand of each subject. After about 5seconds of rest, the hand was blotted dry with a tissue. About 100 μL ofsterile water was topically applied to the back of the right hand ofeach subject in the circled region and spread to cover that area. Afterabout 5 seconds of rest, that hand was blotted dry with a tissue. Asillustrated in FIG. 22 , the Corneometer CM 825 was used to assess andrecord hydration after delivery for both hands. No subjects reported anydiscomfort or discoloration when experiencing the device at the time ofdelivery or after a 24 hour follow-up. Subjects described deliverythrough the device as feeling like a slightly cool mist. After 1 hourand after 2 hours, Subject 3 was reassessed with the Corneometer CM 825,and the results are illustrated in TABLE 1 below.

TABLE 1 Time and Activity Droplette Hydration Topical Hydration 1 Hour:Resting 58% improvement over 0% improvement (back starting hydration tohydration at start) 2 Hours: Had eaten 55% improvement over 11%improvement over lunch and consumed starting hydration baseline (weassume 2 cups of water (we assume some part this is due to food is dueto food and and water consumption water consumption

Results from these studies demonstrate that significantly more water wasdelivered into both young (26 year old) and mature (51 year old) skinwhen using the device compared to topical application. Additionally, thefollow-up with Subject 3 indicated that, once water is delivered usingthe device, the water remains localized to that site and is not quicklyevaporated away compared to topical delivery.

Analysis of the experiments elucidates a probable mechanism for fluiddroplet behavior in the device. Fluid droplets are ejected from thedevice in a turbulent regime with a high Weber number. The Weber numbercompares the effect of inertia to surface tension resulting in a highWeber number meaning that inertial forces dominate relative to surfacetension and dictate behavior of fluid droplet collision. Fluids thatcome into contact with the device can be sucked into the pump where theyundergo droplet breakup because of this fluid regime, rather thanforming into a single stream or a jet. The droplet breakup inside of thepump leads to formation of significantly smaller fluid droplets thatalso have higher velocity and can penetrate into skin rather thanforming a pool on the surface of the skin. As illustrated in FIG. 23 ,data supports this understanding. Fluid droplets that emerge from thedevice are significantly smaller than those formed just using an aerosolof a piezoelectric crystal and retain velocity and elasticity, allowingfluid droplets from the device to penetrate skin and soft tissue.

Calculation of Weber Number

The Weber number is a dimensionless number that compares the relativeeffect of inertial forces to surface tension forces. At higher Webernumbers, fluid droplet formation and breakup is the prominent mechanismthat determines fluid droplet size and distributions.

Inertial forces will scale as approximately ρU²l², while surface forceswill scale as approximately σl. ρ is the density of the fluid (kg/m³). Uis velocity (m/s). l is the characteristic length (typically the fluiddroplet diameter) (m). σ is the surface tension (N/m).

Typically the length scale over which inertia and surface tension act onfluid droplets is the same, so the Weber number may be written as (andthe ratio comes out as):

${We} = \frac{\rho U^{2}l}{\sigma}$

Determination of the Weber number herein considered water beingaerosolized through a pressurized system at room temperature with thefollowing experimental parameters:

ρ=approximately 1000 kg/m³

U=approximately 3.75 m/s

l=approximately 50E-5 m

σ=approximately 0.072 kg/s²

A fluid droplet size can vary between 1 and 1000 μm.

Based on these parameters, a Weber number herein is estimated to beabout 10 to 100, resulting in a regime where there should be significantfluid droplet break up upon collision. For there to be droplet breakup,the Weber number should at least exceed 1 because inertia will thendominate over surface tension. It is estimated that a Weber number ofbetween 10 and 50 will provide the focusing and droplet breakup effectssufficient to enhance penetration of molecules into tissue or cells.

EXAMPLE TEST RESULTS #7

In another experiment, it was verified that peptides that pass through adevice having a configuration as disclosed in FIGS. 1-14 do not getbroken up or damaged. NP-6A solution (768.3 Da) before and after passingthrough the device were subjected to MALDI TOF-TOF MS Analysis. MSspectra of samples were acquired over a mass range of 700 to 1000 m/z(with a “focus mass of 800 m/z). MS spectra, 5000 laser shots, weresummed sub-spectra (50 laser shots×100 across the sample). Asillustrated in FIG. 24 , MALDI-TOF MS spectra of samples showed that themost abundant peptide peak in NP-6A solution before and after passingthrough the device was 768.3 Da indicating that the device does notinduce any significant degradation of the peptide.

EXAMPLE TEST RESULTS #8

In another experiment, p-MIR-GFP vector in aqueous solution (10 μg in500 μl, 3400 kDa in size) was delivered using a device having aconfiguration as disclosed in FIGS. 1-14 onto a monolayer of H9C2 cells,and green fluorescent signal was detected after 72 hours of incubationusing a Leica DMI4000B inverted microscope using a CCD camera. Comparedto delivery using a commercially available chemical transfectionreagent, lipofectamine, the device delivery resulted in less celltoxicity and comparable delivery efficiency, as illustrated in FIG. 25 .

The devices disclosed herein can be designed to be disposed of after asingle use, or they can be designed to be used multiple times. In eithercase, however, the device can be reconditioned for reuse after at leastone use. Reconditioning can include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces, and subsequent reassembly. In particular, the devicecan be disassembled, and any number of the particular pieces or parts ofthe device can be selectively replaced or removed in any combination.Upon cleaning and/or replacement of particular parts, the device can bereassembled for subsequent use either at a reconditioning facility, orby a surgical team immediately prior to a surgical procedure. Oneskilled in the art will appreciate that reconditioning of a device canutilize a variety of techniques for disassembly, cleaning/replacement,and reassembly. Use of such techniques, and the resulting reconditioneddevice, are all within the scope of the present application.

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

What is claimed is:
 1. A method of producing a mist, comprising:activating a device having fluid vaporizer to cause the fluid vaporizerto generate a first mist, wherein a pump of the device draws the firstmist into the pump and the pump generates a second mist that is expelledfrom the device.